The present invention relates to methods and apparatuses for diagnosing or monitoring neurological impairments such as multiple sclerosis.
Slowing of the nervous system occurs as a consequence of both normal aging and neurological impairment. It is well documented that older individuals require a longer period of time to process information relative to younger individuals. It is generally believed that the slowing in the nervous system was mainly related to decision time and motor response because much of the research had focused on motor output (i.e., reaction time) relative to sensory input. However, sensory input and global higher order brain processing may also be significantly affected by neurological impairment, both as a result of injury or disease, or as a result of normal aging.
Multiple sclerosis (MS) is a disease involving neurological impairment which often begins with a history of fluctuating, hard to describe, and seemingly minor, symptoms that family and friends dismiss or discount. These symptoms often resolve without treatment, but continue to return. The initial symptoms of MS are most often: difficulty in walking; abnormal sensations such as numbness or xe2x80x9cpins and needlesxe2x80x9d; and pain and loss of vision due to optic neuritis, an inflammation of the optic nerve. Less common initial symptoms may include: tremor; incoordination; slurred speech; sudden onset of paralysis similar to a stroke; and a decline in cognitive function.
These symptoms are a direct result of demyelination, the destruction of myelinxe2x80x94the fatty sheath that surrounds and insulates nerve fibers in the central nervous system, as well as axonal injury and neuronal death. This impairs transmission of nerve impulses to muscles and other organs.
When doctors suspect multiple sclerosis, they thoroughly evaluate the nervous system as part of the physical examination. Signs that the nervous system isn""t functioning properly, such as uncoordinated eye movements, muscle weakness, or numbness in scattered parts of the body; other findings such as inflammation of the optic nerve; and symptoms that wax and wane make the diagnosis fairly certain.
Diagnostic imaging using magnetic resonance imaging (MRI) is a sensitive technique, possibly revealing areas of the brain that have lost myelin. An MRI scan may even distinguish areas of active, recent demyelination from areas in which demyelination took place some time ago. In an evoked potentials test, electrical responses in the brain are recorded when nerves are stimulated. For example, normally the brain responds to a flash of light or a noise with characteristic patterns of electrical activity; in people with multiple sclerosis, the response may be slower because signal conduction along demyelinated nerve fibers is impaired.
One of the problems in assessing a patient with neurological impairment is that the tests often are expensive (e.g., MRI), time-consuming, and/or invasive. In respect of MS, there is no single measure or test that reliably detects pathologic change. The most common clinical test used to measure disease burden of MS is the extended disability status scale (EDSS) which primarily measures motor output, but it is insensitive to change. Evoked potentials evaluate nerve conduction in some central pathways, but have not proven to be a sensitive measure of disease progression. MRI is useful, but it monitors or detects anatomical changes that follow nerve injury (atrophy and black holes). Moreover, white matter has appeared normal on MRI, yet it is often abnormal when assessed by magnetic resonance spectroscopy (MRS). MRS assesses brain metabolism which is an indication of nerve xe2x80x98healthxe2x80x99 not nerve dysfunction. Since physiologic changes precede irreversible anatomic changes, a tool that assesses physiological function would be valuable in neurological assessment and disease burden.
Sensory symptoms such as numbness, xe2x80x9cpins and needlesxe2x80x9d, pain, loss or interruption of vision (e.g., optic neuritis) tend to precede symptoms of motor dysfunction. Unfortunately, neurological diagnostic/monitoring tests tend to measure motor output (e.g., EDSS) as opposed to measuring the function of sensory pathways. Therefore, tests which measure impairment of sensory pathways, or global higher order brain processing, may detect neurological impairment earlier and more reliably than those tests which measure motor output.
Furthermore, since myelin injury causes reduced nerve conduction, central conduction times may be considered as a useful outcome measure. More specifically, lesions to the pathway connecting the two hemispheres, the corpus callosum, is well noted in the multiple sclerosis literature. Given that interhemispheric transfer times (IHTTs) represent global higher order brain processing, the integration of information between and within hemispheres, deterioration of IHTTs may be an indicator of cognitive dysfunction. There is a need in the art for tests that may measure IHTT as part of a clinical battery for neurological impairment.
The present invention is directed to methods and apparatuses for the diagnosis or monitoring, or both, of neurological impairments by providing an objective measurement of neural function that is relatively inexpensive, easy and quick to administer, and noninvasive. It is an objective technique that also has demonstrable sensitivity to central nerve conduction. The technique may employ a lateralized perspective such that neural function within and between cerebral hemispheres is measured. The lateralized perspective also allows assessment to one side of the body, which is important since many patients and doctors report that symptoms are sometimes lateralized to one side of the body, or to half a visual field.
The present invention was devised to measure sensory functioning of the nervous system without confounding reaction time which includes decision time and motor response time. The invention was also devised so that an estimate of interhemispheric transfer time (IHTT) between cerebral hemispheres could be calculated. High IHTTs would indicate that there is a slowing of central, higher order neural processing as opposed to peripheral neural processing which is typically measured in reaction time tasks. The methods of the present invention demonstrate a sensitivity to both a neurological sensory impairment and interhemispheric transfer dysfunction in patients exhibiting a neurological impairment and therefore may be used in the diagnosis and monitoring of such impairments in patients.
The applicants have found that threshold of simultaneity, which is the minimum temporal separation of two stimuli presented to a patient necessary for a patient to perceive the two stimuli as sequential rather than simultaneous, is greatly increased in patients who suffer from a neurological impairment. Pairs of stimuli are delivered in bilateral or unilateral situations. Interhemispheric transfer is required with bilateral stimulation since each hemisphere receives information regarding the stimulus that was presented to the opposite visual field or to opposite side of the body. That is, since a comparison has to be made regarding the onset of each stimulus, the information needs to be integrated from each hemisphere. The point at which a person perceives the onset of two stimuli as occurring simultaneously is the simultaneity threshold. Thus, the simultaneity threshold is the smallest interval that separates the onset of two stimuli which is perceived by the patient as a separation. The applicants have found that simultaneity thresholds and IHTTs are significantly greater in patients who suffer neurological impairment.
The applicants have further found that the threshold of simultaneity can be quantified and measured against the patient""s own baseline data, and data from groups which include the subject patient, such as groups based on age and sex, in order to measure neural degeneration or regeneration.
Therefore, in one aspect, the invention comprises a method of diagnosis of or monitoring the progression or regression of a neurological impairment in a patient, comprising the steps of: (a) presenting a first sensory stimulus to the patient; (b) presenting a second sensory stimulus to the patient; (c) wherein the first sensory stimulus and second sensory stimulus are temporally separated by a period of time (SOA); (d) determining the patient""s perception of the two stimuli as either simultaneous or sequential for that particular SOA; (e) repeating steps (a) through (d) with different SOA""s until the simultaneity threshold SOA is determined; and (f) comparing the simultaneity threshold SOA to baseline or control data.
The sensory stimuli may be visual, tactile or auditory. In a preferred embodiment, both visual and tactile testing is implemented. The stimuli may be presented bilaterally or unilaterally. In one embodiment, the visual stimuli are red LEDs and the tactile stimuli are punctate stimuli with a blunt pin or rod. The tactile stimuli may be presented to any body part. In one embodiment, the tactile stimuli are delivered to the patient""s fingertips.
Interhemispheric transfer times may be estimated and compared with baseline or control data. IHTTs may be estimated by determining the difference between bilateral and unilateral simultaneity thresholds.
In another aspect, the invention may comprise an apparatus for diagnosing a neurological impairment in a patient, comprising:(a)computer-implemented control means for delivering pairs of sensory stimuli to the patient, including a timing control means, wherein each pair comprises first and second sensory stimuli temporally separated by an SOA;(b)an array of visual stimuli operably connected to the control means; and(c)an array of tactile stimulators operably connected to the control means.